Key considerations for clinical trials in psychopharmacology
Authors: Carlos A. Zarate
Journal: World Psychiatry (2023)

The thoughtful review by Correll et al1 ex­plores the status of drugs for mental disorders with new mechanisms of action cur­rently in testing, and details obstacles to developing such medications. The authors examined established clinical registries and identified ongoing clinical trials of agents that showed the most promise “as emerging from documented superiority over placebo, magnitude of the observed effects, and dem­onstration of requirements for safety and tol­erability”. In aggregate, the list of agents is quite encouraging. The paper, however, does not cover negative trials, although the field can learn much from well-conducted trials of drugs that did not separate from placebo; such studies can rule out a specific target, thereby potentially eliminating the un­nec­essary pursuit of a pathway unlikely to be fruit­ful. The most useful part of the paper is the discussion by this group of well-known in­vestigators of ongoing developments in clinical trial methodology, design and conduct that should be carefully considered when developing and testing pharmacological agents for the treatment of mental disorders. These recommendations, which could be used to de-risk trial programs of novel or repurposed agents, are state-of-the-art and should, if possible, be incorporated as much as possible into planned future trials. While all of these suggestions are very thoughtful, I particularly wish to expand upon two: the importance of early phase 2 proof-of-concept studies and of iden­tifying a treatment's precise mechanism of action. A key and largely unaddressed issue in clinical trials is the ever-increasing placebo-response rates and the resulting diminishment of drug-placebo differences in efficacy over time. As Correll et al point out, solutions such as increasing sample size and adding more study sites have not improved our ability to discern drug efficacy versus placebo, though they have increased the cost of conducting such studies. In this context, although adequately pow­ered phase 2 and 3 studies are certainly ne­cessary at some point, the importance of smaller, well-controlled and well-conducted phase 2A studies should not be minimized. Such studies have the potential to identify an important efficacy signal that would then allow investigators to move forward more confidently with larger and more costly phase 2 studies. As a key example, one of the pivotal studies in the US Food and Drug Administration (FDA)’s approval of valproate for mania included 36 participants (N=17 valproate, N=19 placebo)2. A more recent example concerns the approval of brexanolone for postpartum depression: one of the first reports was a case series of only four women3, and a subsequent small randomized trial had only 21 participants with postpartum depression (N=10 brexanolone, N=11 placebo)4. Ketamine provides another key example: the initial study investigating race­mic ketamine's antidepressant effects was a small, controlled trial of seven participants with major depression, followed by a second study of 17 participants with treatment-resistant depression5, 6. Despite their small size, these two studies were influential in the development and ultimate FDA approval of esketamine for treatment-resistant depression. These examples underscore how astute­ clinical observation and small, well-de­signed, proof-of-concept studies provide a useful strategy for de-risking any novel agent's path to approval. Findings from small early trials can inform go/no-go decisions regarding whether to move forward with larger, well-powered phase 2 studies with effect sizes large enough to survive the elevated placebo rates associated with moving from experimental settings to real-world studies. This approach is of considerable in­terest to a clinical neuroscience industry that seeks to de-risk failures occurring during phas­es 2 and 37. In addition, early proof-of-concept studies help identify critical fea­si­bility, safety and design issues before jump­ing into larger and costlier phase 2 and 3 stud­ies. Correll et al correctly identify the consid­erable discrepancy between indication-based nomenclature and the clinical use of psychotropics. They further note that pharmacological nomenclature is arcane and does not completely relate to mechanisms of action. Important recent efforts have led to the creation of a neuroscience-based no­menclature for psychotropics8. Multiple in­ternational societies and scientific organizations have joined these efforts. Likewise, journals, book publishers and academic curricula have begun to refer to psychotropic medications based on their presumed mech­anisms of action. Such important efforts are likely to facilitate scientific communication and move drug development forward. Nevertheless, our knowledge of drug mechanisms is still in its infancy, and nomenclature is likely to change with new insights or findings. In other words, any given medication's presumed mechanism of action is a rapidly evolving concept. Ketamine provides a salient example. Spe­cifically, ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist. While this mechanism is relevant to keta­mine's an­esthetic properties, the degree to which it underlies its antidepressant properties is a topic of much debate, with evidence on both sides. This question is vital because, if NMDAR an­tagonism does not underlie ketamine's antidepressant effects, then the field – which seeks to develop a safer alternative to ketamine – should cease chasing a target unlikely to be relevant. Indeed, multiple NMDAR antagonists have demonstrated no antidepressant efficacy in treatment-resistant depression9, though some such agents remain in play, including the recently approved AXS-05 (dextromethorphan + bupropion). Although its maker has described NMDAR antagonism as AXS-05's primary mechanism of action, it should be noted that this drug is al­so a sigma-1 agonist, a nicotinic acetylcho­line receptor antagonist, and a serotonin/noradrenaline/dopamine reuptake inhibitor. To date, no significant studies have explored which of these mechanisms might be the most relevant. Because AXS-05 is dis­tinct from most currently available antidepressants, exploring its relevant mechanisms of action may provide novel targets to pursue in clinical trials. An important limitation to progress in this area, however, is that the field has few ways to identify more precise, mechanistically-relevant biomarkers, although some promising ones are currently under investigation. To date, many of our proposed therapeutic targets were identified via in vitro or in vivo non-human assays, so our ability to assess whether a suspected mechanism of action is relevant or not remains limited. For example, no suitable positron emission tomography (PET) ligands are yet available to study potential NMDAR antagonists, even though two NMDAR an­tagonists, esketa­mine and AXS-05, are FDA-approved to treat depression. In conclusion, Correll et al's review thoughtfully addresses some of the pitfalls asso­ci­ated with current methods for developing pharmacological treatments with a novel mech­anism of action. The solutions that the authors propose are likely to increase the availability of novel treatments for our patients, some of which will hopefully be more effective than available ones. Nevertheless, despite the new targets in the pipeline, it should be noted that, with a few key exceptions (ketamine, brexanolone), no new treatment developed in the past several decades for any psychiatric condition has proven significantly superior to existing treatments in the sense of being disease-modifying. In this context, reverse engineering of the new treatments that are identified as unique in some as­pects, such as ketamine – that is, using them as tools to better understand the cellular and molecular mechanisms of the specific disorder under study – might offer the opportunity to develop more effective next-generation treatments. Indeed, such work is already underway.